Platelet-derived growth factor (PDGF) is a disulfide-linked dimer consisting of two related polypeptide chains. designated PDGF A and PDGF B. that are the products of distinct genes. The gene encoding the human PDGF B chain is the normal counterpart of the v-sis oncogene. To develop PDGF dominant negatives and investigate PDGF interchain interactions. the synthesis. assembly. secretion and purification of PDGF heterodimers was studied. PDGF AB was released into culture fluids less efficiently than PDGF AA. but to a greater degree than PDGF BB. Heterodimers between active PDGF A and disabled PDGF B mutants demonstrated that the impaired biologic activity of the B chain was ameliorated or rescued with respect to binding and triggering alpha platelet derived growth factor receptors (PDGFRs). In cells that expressed both receptor types. PDGF AB mutant heterodimers gained substantially in their ability to recruit alpha but not beta PDGFRs. A potently neutralizing monoclonal antibody (mab) to the human alpha PDGFR was developed which recognized alpha PDGFRs in several species, as well as human tumor cell lines. Mab alphaRI also inhibited autocrine growth stimulation of 32D alpha PDGFR transfectants expressing either PDGF AA or PDGF BB. Molecular genetic techniques mapped the alpha PDGFR'S PDGF AA binding domain to contain the mab alphaR1 epitope. The ligand binding domains of immunoglobulin (Ig)-like receptors such as the fibroblast growth factor receptors (FGFRs) and PDGFRs were studied using a novel chimeric Ig fusion protein system. In the case of the keratinocyte growth factor receptor (KGFR). it was shown that high affinity binding sites for related FGF ligands resided within different receptor Ig-like domains. Additionally, betaPDGFR-Ig fusion proteins were used to establish an ELISA-like assay format for identification of competitive antagonists capable of blocking PDGF-mediated responses.